This invention relates to a stable, rapidly soluble, microcrystalline form of cisplatin, and to dry-mix formulations thereof, which, after reconstitution with sterile water, are used by injection in the chemotherapy of cancer.
The platinum compounds are a unique group of compounds in the antineoplastic group of agents. They were first noted to have an antibiotic effect by Rosenberg and his colleagues in 1965 [Rosenberg, B. et. al., Nature (London), 205, 698-699 (1965)] and subsequently found by Rosenberg and his colleagues to be potent antitumor agents in animals [Rosenberg, B. et. al., Nature (London), 222, 385-386 (1969)].
Structurally they represent a complex formed by a central atom of platinum and surrounded by various arrangements of chlorine atoms or ammonia groups in either a cis or trans planar relationship. Two of the more commonly studied platinum compounds are diagrammed below: ##STR1## As can be seen, the compound cis-platinum (II) diamminedichloride has all its chloro and amino groups in a single plane. This compound, now known by the United States Adopted Name (USAN) cisplatin, has been synthesized according to the following reaction: ##STR2## [see Kauffman, G. B. et al., in Inorganic Synthesis, J. Kleinberg (Ed.), pages 239-245, McGraw-Hill Book Co., Inc., New York, 1963].
Breusova-Baidala, Y. G. et al., in Akademia Nauk SSSR, No. 6, pp. 1167-1169 (June 1974), discuss the slow isomerization of cis-platinum (II) diamminedichloride in aqueous solution to the trans form.
Reishus, J. W. and Martin, D. S., in Journal of The American Chemical Society, 83, 2457-2462 (1961), describe the acid hydrolysis of cisplatin at 25.degree. C. and 35.degree. C. These studies were conducted in aqueous solutions at concentrations of 1.5.times.10.sup.-3 M, 2.5.times.10.sup.-3 M and 5.0.times.10.sup.-3 M, which correspond to 0.45, 0.75 and 1.5 mg./ml., respectively. The authors state that there was some ambiguity in locating the origin (i.e. "zero point") for the hydrolysis curves because the samples required from 10 to 30 minutes to dissolve completely even at those low concentrations.
Rozencweig, M. et al., in Annals of Internal Medicine, 86, 803-812 (1977), review the results of various preclinical and clinical investigations of the use of cisplatin in experimental tumors in animals as well as various types of human tumors. They point out that the investigational drug, available to qualified investigators through the Investigational Drug Branch and the Cancer Therapy Evaluation Program of the National Cancer Institute, was supplied as a white lyophilized powder in vials containing 10 mg. of cisplatin, 90 mg. of sodium chloride, 100 mg. of mannitol (U.S.P.) and hydrochloric acid for pH adjustment. When reconstituted with 10 ml. of sterile water for injection (U.S.P.), each ml. of the resulting solution would contain 1 mg. of cisplatin, 10 mg. of mannitol and 9 mg. of NaCl.
Talley, R. W. et al., in Cancer Chemotherapy Reports, 57, 465-471 (1973), describe the results of their Phase I clinical study of the use of cisplatin in the treatment of 65 human patients with a wide variety of neoplasms. As in the preceding publication, the drug was supplied to them by the National Cancer Institute in vials containing 10 mg. of cisplatin, 90 mg. sodium chloride and 100 mg. of mannitol, for reconstitution with 10 ml. of sterile water.
Rossof, A. H. et al., in Cancer, 30, 1451-1456 (1972), describe the results of their use of cisplatin in the treatment of 31 human patients with a variety of tumor types. They state that the drug supplied by the National Cancer Institute was manufactured by Ben Venue Laboratories, Inc. and contained, per vial, 10 mg. of cisplatin, 10 mg. (sic) of mannitol and 9 mg. (sic) of NaCl, and that the yellowish-white powder dissolved readily in 8-10 ml. of sterile water.
Certain information concerning the chemistry and pharmaceutical formulation of cisplatin are given on pages 1-5 and 31-32 of tbe publication entitled "CLINICAL BROCHURE, CIS-PLATINUM (II) DIAMMINEDICHLORIDE (NSC-119875)", H. Handelsman et al., Investigational Drug Branch, Cancer Chemotherapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute (Revised August 1974). Pages 31 and 32 thereof concern the formulation of cisplatin supplied gratis by the N.C.I. to clinicians for their clinical evaluation in the chemotherapy of cancer and read as follows:
______________________________________ PHARMACEUTICAL DATA SHEET NSC-119875 Cis-Diamminedichloroplatinum (II) ______________________________________ Dosage Formulation 10 mg./vial The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial contains 10 mg. of NSC-119875; 90 mg. of Sodium Chloride; 100 mg. of Mannitol and Hydrochloric acid for pH adjustment. Solution Preparation 10 mg./vial When reconstituted with 10 ml. of Sterile Water for Injection, USP, each ml. of the resulting solution will contain 1 mg. of NSC-119875, 10 mg. of Mannitol, and 9 mg. of Sodium Chloride having a pH range of 3.5-4.5. Storage The dry, unopened vials should be stored at refrigeration temperatures (4-8.degree. C.). Stability Intact vials have a provisional stability of one year when stored at refrigeration temperature (4-8.degree. C.). Stability recom- mendations may be adjusted pending com- pletion of a two-year shelf-life study. Reconstitution as recommended results in a pale, yellow solution which is stable for not more than one hour at room tem- perature (22.degree. C.) when exposed to normal room illumination and not more than eight hours at room temperature (22.degree. C.) when protected from light. Reconstituted solutions may form a precipitate after - one hour at refrigeration temperature (4-8.degree. C.). Caution The lyophilized dosage formulations contain no preservatives and therefore it is advised to discard solutions eight hours after reconstitution. ______________________________________
August, 1974 PA0 Clinical Drug Distribution Section PA0 Drug Development Branch